Dynamic U2AF cycling defines two phases of cotranscriptional pre-mRNA splicing

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-09-25 DOI:10.1126/science.adj9141

Changwei Shao, Yajing Hao, Li Jiang, Dong Wang, Rui Wang, Yuanjun Li, Hui Wang, Yaping Ge, Rui Bai, Xiangjuan Du, Xizi Chen, Tan Wu, Lan-Tao Gou, Ruixue Wan, Yanhui Xu, Xiong Ji, Xiang-Dong Fu

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Abstract

Distinguishing functional splice sites from abundant cryptic sites in precursor messenger RNAs (pre-mRNAs) represents a fundamental challenge in decoding mammalian genomes. We demonstrate that the specific RNA polymerase II (Pol II) subunit RPB9 directly interacts with the 3′ AG dinucleotide binding factor U2AF1 to initiate 3′ splice site recognition. Combined with recent structural insights into Pol II–mediated 5′ splice site selection, these findings support a cotranscriptional mechanism to recognize paired 3′ and 5′ splice sites across individual exons. These initial exon definition events facilitate the recruitment of U2AF2 to heterodimerize with U2AF1, which also triggers U2AF1 release from elongating Pol II. Collectively, these results reveal dynamic U2AF cycling that partitions Pol II subunit–facilitated splice site recognition and subsequent Pol II–independent spliceosome assembly steps during cotranscriptional splicing.

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动态U2AF循环定义了共转录pre-mRNA剪接的两个阶段

区分前体信使rna （pre- mrna）的功能剪接位点和丰富的隐式位点是解码哺乳动物基因组的一个基本挑战。我们证明了特异性RNA聚合酶II （Pol II）亚基RPB9直接与3 ‘ AG二核苷酸结合因子U2AF1相互作用以启动3 ’剪接位点识别。结合最近对Pol ii介导的5 ‘剪接位点选择的结构见解，这些发现支持了一种识别单个外显子中配对的3 ’和5 '剪接位点的共转录机制。这些初始外显子定义事件促进了U2AF2与U2AF1的异二聚化，这也触发了U2AF1从延长Pol II中释放。总的来说，这些结果揭示了在共转录剪接过程中，动态U2AF循环分割了Pol II亚基促进的剪接位点识别和随后的Pol II非依赖性剪接体组装步骤。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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